This invention relates to sodium-hydrogen exchanger type 1 (NHE-1) inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat for example, ischemia particularly, perioperative myocardial ischemic injury in mammals, including humans.
Mycardial ischemic injury can occur in out-patient as well as in perioperative settings and can lead to the development of sudden death, myocardial infarction or congestive heart failure. There is an unmet medical need to prevent or minimize myocardial ischemic injury, particularly perioperative myocardial infarction. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
Pharmacological cardioprotection would reduce the incidence and progression of myocardial infarction and dysfunction occurring in these surgical settings (perioperatively). In addition to reducing myocardial damage and improving post-ischemic myocardial function in patients with ischemic heart disease, cardioprotection would also decrease the incidence of cardiac morbidity and mortality due to myocardial infarction and dysfunction in patients “at risk” (such as greater than 65 years, exercise intolerant, coronary artery disease, diabetes mellitus, hypertension) that require non-cardiac surgery.
The mechanism(s) responsible for the myocardial injury observed after ischemia and reperfusion is not fully understood.
A variety of publications have disclosed the use of guanidine derivatives as useful for the treatment of, for example arrhythmias.
U.S. Pat. No. 5,698,581, granted Dec. 16, 1997 (EP 676395 A2 published 1995), discloses certain substituted N-heteroarylguanidines as inhibitors of the (Na+/H+) exchange transport system useful for the treatment of, for example, arrhythmias.
EP 803 501 A1, published Oct. 10, 1997, discloses substituted guanidine derivatives useful as (Na+/H+) exchange inhibitors.
WO 94/26709 discloses guanidine derivatives as inhibitors of (Na+/H+) exchange in cells.
PCT/JP97/04650 application published on Jun. 25, 1998 discloses N-[(substituted five-membered heteroaryl)carbonyl]guanidine compounds which are stated to be useful as inhibitors of Na+/H+ exchange and consequently effective for the treatment of various diseases such as hypertension, arrhythmia, angina pectoris, myocardial infarct, arteriosclerosis, and complications of diabetes.
Thus, there is clearly a need and a continuing search in this field of art for treatments for perioperative myocardial ischemia.